Hypercholesterolemia is a risk factor for atherosclerotic heart disease. Atherosclerotic heart disease represents the major cause for death and cardiovascular morbidity in the world (Lipid Research Clinics Program. J. Am. Med. Assoc., 1984, 251, 351 or 365). Recently, HMG-CoA reductase inhibitors have been used as the hypocholesterolemic agents in clinical. HMG-CoA reductase inhibitors are shown to have a potent serum hypocholesterolemic activity, however, they are also reported to have unfavorable side effects (Mevacor in Physician's Desk Reference, 49th ED, Medical Economics Date Production Company, 1995, 1584). Therefore, the potent and safety serum hypocholesterolemic agents are desired.
It has been reported that naturally occuring glycosides have serum hypocholesterolemic activity (M. A. Farboodniay Jahromi et al., J. Nat. Prod., 1993, 56, 989., K. R. Price, The Chemistry and Biological Significance of Saponins in Fords and Feeding Stuffs. CRC Critical Reviews in Food Science and Nutrition, CRC Press, 1987, 26, 27). It is considered that these glycosides reduce serum cholesterol levels due to the inhibition of cholesterol absorption in small intestine (P. A. McCarthy et al., J. Med. Chem., 1996, 39, 1935). Additionally, some β-lactam compounds are reported its hypocholesterolemic activity (S. B. Rosenblum et al., J. Med. Chem., 1998, 41, 973, B. Ram et al., Indian J. Chem., 1990, 29B, 1134. U.S. Pat. No. 4,893,597).
The β-Lactam compounds have a weak inhibitiory activity on cholesterol absorption themselves, and further the glucuronide of the β-lactam compounds are more potent than the parent β-lactams. In the absorption process, the β-lactam compounds are rapid glucuronidated in small intestine after oral administration, and the resulting glucuronide derivatives are secreted through bile-duct to small intestine. These β-lactam-O-glucuronic acid conjugated derivatives are located to mucosal layer in small intestine, a site of action, and inhibit cholesterol absorption (M. van Heek et al., Brit. J. Pharmacol., 2000, 129, 1748, J. Pharmacol. Exp. Ther., 1997, 283, 157). Because of the above mentioned β-lactam compounds show serum hypocholesterolemic activity in small intestine by β-lactam-O-glucuronate conjugated derivatives, the hypocholesterolemic activities of these compounds incorporating glucose or glucuronic acid derivatives were synthesized (W. D. Vaccaro et al., Bioorg. Med. Chem. Lett., 1998, 8, 313). However, it is considered that the O-glycoside bonds in these compounds are readily hydrolyzed with glycosidase existed in small intestine after oral administration, and it is supposed the hypocholesterolemic activities of these compounds in small intestine will be reduced. Thinking about the active site of these β-lactams is mucosal layer in small intestine, the better cholesterol absorption inhibitors are required to act just only in small intestine with high efficacy and long duration. It is expected that ideal cholesterol absorption inhibitors are not to be absorbed in small intestine and eliminated without absorption in small intestine so that side effects will be reduced after the absorption in small intestine.
The principal object of the present invention is the provision of novel hypocholesterolemic agents having β-lactam moiety and C-glycoside in the molecules, which is stable to metabolism by glycosidase and hydrolysis with acids or bases. Namely, the object of the present invention is the provision of hybrid molecules with β-lactam and C-glycoside as hypocholesterolemic agents.